title: Localization of HPV-18 E2 at mitochondrial membranes induces ROS release and modulates host cell metabolism.
abstract: Papillomavirus E2 proteins are predominantly retained in the nuclei of infected cells, but oncogenic (high-risk) HPV-18 and 16 E2 can shuttle between the host nucleus and cytoplasm. We show here that cytoplasmic HPV-18 E2 localizes to mitochondrial membranes, and independent mass spectrometry analyses of the E2 interactome revealed association to the inner mitochondrial membrane including components of the respiratory chain. Mitochondrial E2 association modifies the cristae morphology when analyzed by electron microscopy and increases production of mitochondrial ROS. This ROS release does not induce apoptosis, but instead correlates with stabilization of HIF-1α and increased glycolysis. These mitochondrial functions are not shared by the non-oncogenic (low-risk) HPV-6 E2 protein, suggesting that modification of cellular metabolism by high-risk HPV E2 proteins could play a role in carcinogenesis by inducing the Warburg effect.
authors.affiliation: Papillomavirus Regulation and Cancer, Institute of Medical Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
authors.forename: Deborah
authors.initials: D
authors.lastname: Lai
authors.forename: Chye Ling
authors.initials: CL
authors.lastname: Tan
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.forename: Ling Shih
authors.initials: LS
authors.lastname: Quek
authors.forename: Wenlong
authors.initials: W
authors.lastname: Nei
authors.forename: Françoise
authors.initials: F
authors.lastname: Thierry
authors.forename: Sophie
authors.initials: S
authors.lastname: Bellanger
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D003593:Cytoplasm / Q000378:metabolism / Q000821:virology; D006019:Glycolysis / Q000502:physiology; D052161:Human papillomavirus 18 / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000821:virology; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009856:Oncogene Proteins, Viral; D017382:Reactive Oxygen Species; D014764:Viral Proteins